Drugs that have abuse liability in humans typically serve as positive reinforcers to maintain and strengthen behavior leading to their administration in animals and serve as discriminative stimuli controlling two-lever choice behavior. Experiments are being conducted to assess neurobiological and behavioral mechanisms underlying drug self-administration behavior and behavior controlled by drugs as discriminative stimuli in rats and monkeys and the ability of pharmacological or behavioral manipulations to modify such behavior. Tobacco dependence is the leading preventable cause of mortality in the world and nicotine appears to be the main critical psychoactive component in establishing and maintaining tobacco dependence. PPARa are nuclear receptors that are strongly expressed in many tissues including specific areas of the brain where nicotine works to produce its rewarding effects. We have previously shown that experimental drugs that activate PPARa block nicotine-induced activation of the brain mesolimbic dopamine reward system in rats, and decrease nicotine-seeking behavior in rats and monkeys, suggesting that PPARa agonists might serve as effective anti-smoking medications. The fibrates are a class of PPARa-activating medications that are widely prescribed to improve lipid profiles and prevent cardiovascular disease, but these drugs have not been tested in animal models of nicotine reward. We examined the effects of clofibrate, a representative of the fibrate class, on reward-related behavioral, electrophysiological, and neurochemical effects of nicotine in rats and squirrel monkeys (Panlilio et al., 2012). Clofibrate prevented the acquisition of nicotine-taking behavior in naive animals, substantially decreased nicotine taking in experienced animals, and counteracted the relapse-inducing effects of re-exposure to nicotine or nicotine-associated cues after a period of abstinence. In the central nervous system, clofibrate blocked nicotines effects on neuronal firing in the ventral tegmental area and on dopamine release in the nucleus accumbens shell. All of these results suggest that fibrate medications might promote smoking cessation. We have previously shown that inhibition of fatty acid amide hydrolase (FAAH) attenuates reinstatement of nicotine seeking induced by both nicotine priming and nicotine-associated cues in abstinent rats. FAAH is responsible for the hydrolysis of the endogenous endocannabinoid anandamide, as well as other non cannabinoid ligands such as oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). Since OEA/PEA can attenuate both nicotine-taking and nicotine-seeking behavior, the specific role of anandamide relative to OEA and PEA remains unclear. We have now evaluated the impact of the selective anadamide uptake inhibitor, VDM11, which elevates anandamide levels without affecting levels of OEA/PEA, on nicotine-taking and nicotine-seeking behavior (Gamaleddin et al., 2011). We used the nicotine intravenous self administration paradigm to assess the effect of VDM11 on nicotine taking using fixed and progressive ratio schedules of intravenous nicotine reinforcement as well as on reinstatement of nicotine seeking induced by nicotine priming and nicotine associated cues. VDM11 did not affect levels of responding for nicotine under fixed-ratio and progressive-ratio schedules of reinforcement. In contrast, it dose dependently attenuated reinstatement of nicotine-seeking behavior induced by nicotine associated cues and nicotine priming. This suggests that anandamide uptake inhibitors can prevent relapse to nicotine-seeking behavior independent of effects on PPARa and should be tested in human smoking cessation trials. Another approach to the pharmacological facilitation of smoking cessation is the use of the clinically approved varenicline (Champix), a nicotinic partial agonist. We evaluated varenicline on the subjective effects of nicotine (drug discrimination), motivation for nicotine self-administration under a progressive-ratio schedule and cue-induced reinstatement of previously extinguished nicotine-seeking in rats (Le Foll et al., 2011). Effects on motor performance were also assessed in rats trained to discriminate nicotine from saline under a fixed-ratio schedule of food delivery and in rats trained to respond for food under a progressive-ratio schedule. With a 2 hour pretreatment time, no effect was noted on motor performance, but varenicline blocked the ability of the animals to discriminate between nicotine doses and varenicline dose-dependently blocked the motivation to self-administer nicotine under the progressive-ratio schedule, but no effect was found on the motivation to respond for food under the progressive-ratio schedule. Varenicline also reduced the ability of cue presentation to induce nicotine-seeking. These findings support the dual effects of varenicline (reducing both nicotine-taking behavior and relapse to nicotine-seeking behavior) that contribute to its efficacy in treating human smokers. Characterization of the crosstalk between nicotine addiction and the cannabinoid system may have significant implications for our understanding of the neurobiological mechanisms underlying nicotine dependence. Two types of cannabinoid receptors (CB1 and CB2) have been identified. CB1 receptors are expressed in the brain and modulate drug taking and drug seeking for various drugs of abuse, including nicotine. Cannabinoid CB2 receptors have been recently identified in the brain and have been proposed to play a functional role in mental disorders and drug addiction. We have explored the role of CB2 receptors on intravenous nicotine self administration under two schedules of reinforcement (fixed-ratio and progressive-ratio schedules) and on nicotine-seeking behavior induced by nicotine priming or by nicotine-associated cues (Gamaleddin et al., 2012b). For this, we evaluated the effects of various doses of the selective cannabinoid CB2 receptor antagonist AM630 (1.25 to 5 mg/kg) and the CB2 agonist AM1241 (1 to 10 mg/kg) on these behavioral responses in rats. Different groups of rats were trained to lever press for nicotine at a unit dose of 30 g/kg/infusion. Subsequently, animals were randomized using a Latin-square design and injected with either AM1241 or AM630 using a counterbalanced within subject design. Administration of the CB2 receptor ligands did not affect either nicotine-taking or nicotine-seeking behavior. Our results do not support the involvement of cannabinoid CB2 receptors in nicotine-taking or nicotine-seeking behavior.